X-Message-Number: 25701
Date: Sat, 19 Feb 2005 20:59:30 -0800 (PST)
From: Doug Skrecky <>
Subject: could vitamin K2 extend lifespan?

J Neurosci. 2003 Jul 2;23(13):5816-26.
Novel role of vitamin k in preventing oxidative injury to developing
oligodendrocytes and neurons.
    Oxidative stress is believed to be the cause of cell death in
multiple disorders of the brain, including perinatal hypoxia/ischemia.
Glutamate, cystine deprivation, homocysteic acid, and the glutathione
synthesis inhibitor buthionine sulfoximine all cause oxidative injury
to immature neurons and oligodendrocytes by depleting intracellular
glutathione. Although vitamin K is not a classical antioxidant, we
report here the novel finding that vitamin K1 and K2 (menaquinone-4)
potently inhibit glutathione depletion-mediated oxidative cell death in
primary cultures of oligodendrocyte precursors and immature fetal
cortical neurons with EC50 values of 30 nm and 2 nm, respectively. The
mechanism by which vitamin K blocks oxidative injury is independent of
its only known biological function as a cofactor for
gamma-glutamylcarboxylase, an enzyme responsible for posttranslational
modification of specific proteins. Neither oligodendrocytes nor neurons
possess significant vitamin K-dependent carboxylase or epoxidase
activity. Furthermore, the vitamin K antagonists warfarin and
dicoumarol and the direct carboxylase inhibitor 2-chloro-vitamin K1
have no effect on the protective function of vitamin K against
oxidative injury. Vitamin K does not prevent the depletion of
intracellular glutathione caused by cystine deprivation but completely
blocks free radical accumulation and cell death. The protective and
potent efficacy of this naturally occurring vitamin, with no
established clinical side effects, suggests a potential therapeutic
application in preventing oxidative damage to undifferentiated
oligodendrocytes in perinatal hypoxic/ischemic brain injury.

Biochem Pharmacol. 1997 Oct 15;54(8):871-6.
The potent antioxidant activity of the vitamin K cycle in microsomal
lipid peroxidation.
            In the vitamin K cycle, vitamin K-hydroquinone, the active
cofactor for gamma-glutamylcarboxylase, is continuously regenerated.
The successive pathways contain oxidation of the hydroquinone to the
epoxide, followed by reduction to the quinone and reduction to the
hydroquinone. Vitamin K-hydroquinone is a potent radical scavenging
species (Mukai et al., J Biol Chem 267: 22277-22281, 1992). We tested
the potential antioxidant activity of the vitamin K cycle in lipid
peroxidation reactions (thiobarbituric acid reactive substances, TBARS)
in rat liver microsomes. As prooxidant we used Fe2+/ascorbate,
NADPH-Fe3+/ATP, and NADPH/CCl4. Vitamin K (< or = 50 microM) on its own
did not influence the formation of TBARS. In combination with 1 mM
dithiothreitol (DTT), the reductive cofactor for the microsomal enzyme
vitamin K epoxide reductase, vitamin K suppressed lipid peroxidation
with a concentration that blocked the maximal response by 50% (IC50) of
ca. 0.2 microM. Vitamin K1 (phylloquinone) and vitamin K2
(menaquinone-4) were equally active. Warfarin (5 microM) and
chloro-vitamin K (50 microM), inhibitors of vitamin K epoxide reductase
and gamma-glutamylcarboxylase, respectively, were able to completely
abolish the antioxidant effect. Lipid peroxidation was inversely
related to the amount of vitamin K hydroquinone in the reaction.
Vitamin K epoxide reductase seemed sensitive to lipid peroxidation,
with half of the activity being lost within 10 min during oxidation
with NADPH/CCl4. The inactivation could be attenuated by antioxidants
such as vitamin E, reduced glutathione, and menadione and also by a K
vitamin in combination with DTT, but not by superoxide dismutase and
catalase. The results show that the vitamin K cycle could act as a
potent antioxidant, that the active species in all probability is
vitamin K-hydroquinone, and that the primary reaction product is the
semiquinone. The results also show that the reaction product is
processed in the vitamin K cycle to regenerate vitamin
K-hydroquinone.

Brain Res Dev Brain Res. 1993 May 21;73(1):17-23.
Age-dependent survival-promoting activity of vitamin K on cultured CNS
neurons.
              Neurons from the central nervous system (CNS) of rat
embryos die within several days when seeded at a low density of 10(4)
cells/cm2 and cultured in a serum-free defined medium. Using these
culture systems, we searched for agents to promote the survival of
these neurons. As a consequence, a fat-soluble vitamin, vitamin K1, was
found to possess such kind of activity: more than 50% of the cortical
neurons from 19-day-old rat embryos could survive for 4 days in the
presence of vitamin K1, whereas almost all neurons died in its absence.
The survival-promoting effect of vitamin K1 was found on neurons from
not only cortex, but also hippocampus, striatum, and septum. In
addition to vitamin K1, vitamin K2 and K3 also showed the same effect
on cortical neurons. The effect of vitamins K1 and K2 was observed at
concentrations from 10(-8) to 10(-6) M, and that of vitamin K3 was
slightly detected at 10(-6) M. Furthermore, we examined the effect on
the neurons from 16- and 21-day-old embryos, too. The activity of
vitamin K1 was weaker toward the neurons from 21-day-old embryos
compared with that toward 19-day-old ones, and was not recognized
toward 16-day-old ones. These results suggest the potential role of the
K vitamins on the maintenance of the survival of CNS neurons during the
later stages of embryogenesis in vivo.

Biochim Biophys Acta. 1996 Nov 14;1298(1):87-94.
Natural prenylquinones inhibit the enzymes of the vitamin K cycle in
vitro.
               Vitamin K belongs to a class of compounds commonly known
as prenylquinones. Three other prenylquinones which are abundantly
found in food are plastoquinone-9, ubiquinone-9 and ubiquinone-10.
Using in vitro assay systems, it was recently found that synthetic
derivatives of prenylquinones inhibit the vitamin K-dependent enzyme
gamma-glutamylcarboxylase and, to a lesser extent, the vitamin
K-epoxide reductase. In this paper we describe how natural
prenylquinones affect the vitamin K-dependent enzymes in vitro. All
three prenylquinones were found to inhibit both the vitamin K-dependent
carboxylase and the K-epoxide reductase in a rat as well as in a cow
liver system; 50% inhibition was obtained at concentrations in the
micromolar range. On the basis of their respective standard redox
potentials, a possible mechanism for the inhibitory effect of
prenylquinones on the carboxylase enzyme is put forward. It is
concluded that natural prenylquinones are potential antagonists of
vitamin K and may interfere with vitamin K-dependent reactions in
vivo.

Liver cancer vs vitamin K2
JAMA. 2004 Jul 21;292(3):358-61.
Role of vitamin K2 in the development of hepatocellular carcinoma in
women with viral cirrhosis of the liver.
       CONTEXT: Previous findings indicate that vitamin K2
(menaquinone) may play a role in controlling cell growth. OBJECTIVE: To
determine whether vitamin K2 has preventive effects on the development
of hepatocellular carcinoma in women with viral cirrhosis of the liver.
DESIGN, SETTING, AND PARTICIPANTS: Forty women diagnosed as having
viral liver cirrhosis were admitted to a university hospital between
1996 and 1998 and were randomly assigned to the treatment or control
group. The original goal of the trial was to assess the long-term
effects of vitamin K2 on bone loss in women with viral liver cirrhosis.
However, study participants also satisfied criteria required for
examination of the effects of such treatment on the development of
hepatocellular carcinoma. INTERVENTIONS: The treatment group received
45 mg/d of vitamin K2 (n = 21). Participants in the treatment and
control groups received symptomatic therapy to treat ascites, if
necessary, and dietary advice. MAIN OUTCOME MEASURE: Cumulative
proportion of patients with hepatocellular carcinoma. RESULTS:
Hepatocellular carcinoma was detected in 2 of the 21 women given
vitamin K2 and 9 of the 19 women in the control group. The cumulative
proportion of patients with hepatocellular carcinoma was smaller in the
treatment group (log-rank test, P =.02). On univariate analysis, the
risk ratio for the development of hepatocellular carcinoma in the
treatment group compared with the control group was 0.20 (95%
confidence interval [CI], 0.04-0.91; P =.04). On multivariate analysis
with adjustment for age, alanine aminotransferase activity, serum
albumin, total bilirubin, platelet count, alpha-fetoprotein, and
history of treatment with interferon alfa, the risk ratio for the
development of hepatocellular carcinoma in patients given vitamin K2
was 0.13 (95% CI, 0.02-0.99; P =.05). CONCLUSION: There is a possible
role for vitamin K2 in the prevention of hepatocellular carcinoma in
women with viral cirrhosis.

J Nutr. 2004 Nov;134(11):3100-5.
Dietary intake of menaquinone is associated with a reduced risk of
coronary heart disease: the Rotterdam Study.
         Vitamin K-dependent proteins, including matrix Gla-protein,
have been
shown to inhibit vascular calcification. Activation of these proteins
via carboxylation depends on the availability of vitamin K. We examined

whether dietary intake of phylloquinone (vitamin K-1) and menaquinone
(vitamin K-2) were related to aortic calcification and coronary heart
disease (CHD) in the population-based Rotterdam Study. The analysis
included 4807 subjects with dietary data and no history of myocardial
infarction at baseline (1990-1993) who were followed until January 1,
2000. The risk of incident CHD, all-cause mortality, and aortic
atherosclerosis was studied in tertiles of energy-adjusted vitamin K
intake after adjustment for age, gender, BMI, smoking, diabetes,
education, and dietary factors. The relative risk (RR) of CHD mortality
was reduced in the mid and upper tertiles of dietary menaquinone
compared to the lower tertile [RR = 0.73 (95% CI: 0.45, 1.17) and 0.43
(0.24, 0.77), respectively]. Intake of menaquinone was also inversely
related to all-cause mortality [RR = 0.91 (0.75, 1.09) and 0.74 (0.59,
0.92), respectively] and severe aortic calcification [odds ratio of
0.71 (0.50, 1.00) and 0.48 (0.32, 0.71), respectively]. Phylloquinone
intake was not related to any of the outcomes. These findings suggest
that an adequate intake of menaquinone could be important for CHD
prevention.

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